Abstract H2O2 is a major form of reactive oxygen species (ROS) produced by mitochondria. Recent data indicate that increased mitochondrial H2O2 is associated with pathogenesis of Alzheimer's disease (AD) and could facilitate AD pathogenesis by inducing oxidative damage and by altering cell signaling to affect amyloidogenesis. Although targeted removal of mitochondrial ROS has been proposed as a preventive/therapeutic strategy for AD, whether reducing mitochondrial H2O2 can retard pathogenesis of AD is unknown. Peroxiredoxin 3 (Prdx3/Prx3) is a peroxidase specializing in scavenging H2O2 in mitochondria and is also implicated to be important for protection against neurodegenerative diseases. We have recently generated transgenic mice overexpressing Prdx3, and our data indicate that transgenic mice overexpressing Prdx3 have reduced mitochondrial H2O2 levels that are correlated with reduced mitochondrial oxidative damage and decreased activities of 2- and 3- secretases in brain. Thus, our results indicate that overexpression of Prdx3 is effective in reducing mitochondrial H2O2 and that transgenic mice overexpressing Prdx3 will allow us to test the preventive and therapeutic potential of reducing mitochondrial H2O2 for AD. Using APP transgenic mice overexpressing Prdx3 in this project, we will test the following hypothesis: reducing mitochondrial H2O2 by overexpression of Prdx3 will improve mitochondria functions, ameliorate cognition impairment and reduce amyloidogenesis. The hypothesis will be tested in four Specific Objectives: 1. To determine if reducing mitochondrial H2O2 improves mitochondria functions in APP transgenic mice. 2. To determine if reducing mitochondrial H2O2 reduces oxidative damage and changes cell signaling in APP transgenic mice. 3. To determine if reducing mitochondrial H2O2 ameliorates cognitive impairment and decreases amyloidogenesis in APP transgenic mice. 4. To determine if reducing mitochondrial H2O2 can retard progression of AD after the onset of disease. In Specific Objective 4, a novel APP transgenic mouse model with inducible overexpression of Prdx3 will be generated and used to determine whether overexpressing of Prdx3 can slow or reverse the progression of cognition deficit and A( accumulation after the development of these adverse phenotypes. The data collected from this project will provide the first direct evidence about whether reducing mitochondrial H2O2 is effective for retarding AD pathogenesis and whether Prdx3 could serve as a target for AD prevention and therapy. Alzheimer's disease is of special importance to the veteran population because the incidence of Alzheimer's disease appears to be elevated by conditions encountered by our service men and women during deployment such as traumatic brain injury. Data collected in this study may lead to new preventive and therapeutic approaches for AD, which will benefit our military service men and women. 1 PUBLIC HEALTH RELEVANCE: Project Narrative Increased risk of Alzheimer's disease is a serious concern for our military service men and women. This study is designed to test the effectiveness of a novel prevention and therapy strategy for Alzheimer's disease. 1